Drospirenone: Pharmacology and Pharmacokinetics of a Unique Progestogen
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Contraception 62 (2000) 29–38 Original research article Drospirenone: pharmacology and pharmacokinetics of a unique progestogen Rolf Krattenmacher* Berlex Laboratories, 300 Fairfield Road, Wayne, NJ 07470 USA Received 20 March 2000; received in revised form 18 May 2000; accepted 22 May 2000 Abstract The pharmacology and pharmacokinetics of drospirenone, a unique progestogen, are reviewed in this paper. Unlike other progestogens, drospirenone, an analogue of spironolactone, has biochemical and pharmacologic profiles similar to endogenous progesterone, especially regarding antimineralocorticoid and antiandrogenic activities. Drospirenone counteracts the estrogen-induced stimulation of the renin- angiotensin-aldosterone system and blocks testosterone from binding to androgen receptors. Because of these characteristics, it has the potential to reduce body weight, blood pressure, and low-density lipoprotein levels and to enhance high-density lipoprotein levels. As a combination oral contraceptive, drospirenone with ethinyl estradiol is effective and has positive effects on weight and lipid levels. Additionally, it relieves menstrually related symptoms (e.g., negative affect and water retention) that are commonly observed with other combination oral contraceptives. Based on the biochemical and pharmacodynamic data, drospirenone appears to be a viable alternative to the currently available progestogens. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Drospirenone; Progestogen; Oral contraceptive; Renin-angiotensin-aldosterone system; premenstrual syndrome 1. Introduction taining these progestogens may be due, in part, to the absence of these specific antihormone characteristics Improving the safety and tolerability of oral contra- [1,7–9]. These effects include breast tenderness, weight ceptives (OCs) without affecting efficacy has been a gain, increased blood pressure (BP), and mood swings. major research goal for over 20 years. Developing new Adverse effects such as these are the major reason why progestogens has been considered one means of achiev- women discontinue the use of OCs [8]. ing this goal [1,2]. Ideally, a progestogen should have a Drospirenone is an analogue of the aldosterone antag- pharmacologic profile similar to progesterone. Currently onist, spironolactone, and is a unique progestogen [10]. available progestogens are structurally related to either The pharmacologic profile of drospirenone is more 19-nortestosterone (e.g., norethisterone, norethisterone closely related to that of progesterone, especially with acetate, levonorgestrel, gestodene, desogestrel, norgesti- regard to antimineralocorticoid and antiandrogenic activ- ities, than that of any other synthetic progestogen [11– mate, and dienogest) or 17␣-hydroxyprogesterone (e.g., 14]. This suggests that adverse effects commonly ob- medroxyprogesterone acetate, megestrol acetate, chlor- served with combination OCs may be decreased with an madinone acetate, and cyproterone acetate) [3.4]. While OC containing drospirenone. In a recent study, the con- some of these agents have antiandrogenic properties traceptive efficacy and adverse effects of drospirenone/ (e.g., dienogest, cyproterone acetate, megestrol acetate, ethinyl estradiol combination treatment were evaluated and chlormadinone acetate), they all lack antimineralo- with favorable results [2]. corticoid activity when used in clinically relevant dos- The purpose of this article is to review the distinctive ages [3,5,6]. Adverse effects associated with OCs con- biochemical and pharmacologic characteristics and pharma- cokinetics of drospirenone. In addition, contraceptive effi- cacy and the potential health benefits beyond contraception * Correspondence. Tel.: ϩ1-973-305-5324; fax: ϩ1-973-305-5340. associated with drospirenone/ethinyl estradiol will be E-mail address: [email protected] (R. Krattenmacher). discussed. 0010-7824/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S0010-7824(00)00133-5 30 R. Krattenmacher / Contraception 62 (2000) 29–38 Fig. 1. Chemical structures of spironolactone and drospirenone and major drospirenone plasma metabolites. (Data on file, Berlex Laboratories, Wayne, NJ, USA.) 2. Biochemistry says. Relative binding affinity values of these reference compounds were arbitrarily set at 100%. Results of both the Drospirenone (6,7,15,16-dimethylene-3-oxo-17␣- animal and human steroid receptor binding assays are sum- pregn-4-ene-21,17 carbolactone) is an analogue of the an- marized in Table 1. Of note, (1) drospirenone demonstrated timineralocorticoid spironolactone (Fig. 1) that is synthe- a relative binding affinities of 19% to the human and 40% to sized from androstenolone [10,15,16]. A comprehensive, the rabbit progesterone receptor; (2) drospirenone and pro- comparative biochemical characterization of drospirenone gesterone have high relative binding affinities for the min- and progesterone examined their interaction with a series of eralocorticoid receptor (500% and 1000% for the human classical steroid hormone receptors such as the progester- receptor for drospirenone and progesterone, respectively; one, androgen, glucocorticoid, mineralocorticoid, and estro- both 100% for the rat receptor); (3) both progestogens have gen receptors [10]. The relative binding affinities of dro- Յ3% relative binding affinity to the androgen receptor in all spirenone and progesterone to these receptors were models; (4) drospirenone exhibits a low relative binding determined using cytosol fractions containing the expres- affinity to the glucocorticoid receptor (1% and 3% for the sion vector for the respective animal (rat or rabbit) [10] or animal and human receptor, respectively), whereas proges- human steroid receptor. (Data on file, Schering AG, Berlin, terone has some binding affinity to this receptor (11% and Germany.) The radiolabeled reference compounds for the 35% for the animal and human receptor, respectively); and progesterone, androgen, mineralocorticoid, glucocorticoid, (5) neither drospirenone nor progesterone demonstrate sig- and estrogen receptors were progesterone, methyltrien- nificant binding to the estrogen receptor [10]. (Data on file, olone, aldosterone, dexamethasone, and estradiol, respec- Schering AG, Berlin, Germany.) In contrast, other proges- tively, in both the human and animal receptor binding as- togens such as gestodene, 3-ketodesogestrel (active metab- R. Krattenmacher / Contraception 62 (2000) 29–38 31 Table 1 Relative binding affinities (RBA) of progesterone and drospirenone to steroid hormone receptors [10]a RBA (%) Receptor Progesteron Androgen Mineralocorticoid Glucocorticoid Estrogen recptor receptor receptor receptor receptor Human Rabbit Human Rat Human Rat Human Rat Human Rat Drospirenone 19 40 2 1 500 100 3 1 Ͻ0.5 nc* Progesterone 100 100 3 1 1000 100 35 11 Ͻ0.5 nc aHuman data on file, Schering AG, Berlin, Germany. *nc ϭ no competition. The radiolabeled reference compounds for the progesterone, androgen, mineralocorticoid, glucocorticoid, and estrogen receptors were progesterone, methyltrienolone, aldosterone, dexamethasone, and estradiol, respectively in both the human and animal receptor binding assays. RBA vales of these reference compounds were arbitrarily set at 100%. olite of desogestrel), and levonorgestrel have different re- spirenone has antiandrogenic activity which is explained by ceptor-binding profiles than drospirenone and progesterone competitive binding to the androgen receptor and is intrinsic [17]. All three progestogens have demonstrated higher bind- to its molecular structure; this direct antiantiandrogenic ef- ing affinities to both the progesterone and androgen receptor fect is in addition to the more indirect antiandrogenic effect than progesterone or drospirenone. Additionally, levonorg- of progestogens in general, that is mainly explained by the estrel and 3-ketodesogestrel have lower binding affinities to suppression of androgen production from the adrenals or the mineralocorticoid receptor than either progesterone or ovaries. Drospirenone shows no glucocorticoid and antiglu- drospirenone, whereas gestodene has a greater binding af- cocorticoid activity, whereas progesterone exhibits weak finity to this receptor than progesterone or drospirenone. glucocorticoid-receptor–mediated agonistic activity but not The effects of drospirenone and progesterone on andro- antagonist activity [10]. Overall, the results from the ste- gen-, glucocorticoid-, and mineralocorticoid-receptor–me- roid-binding and transactivation assays demonstrate that the diated induction of transcription were also evaluated using biochemical profile of drospirenone is similar to that of in vitro transactivation assays [10]. These assays were per- progesterone, especially regarding its antimineralocorticoid formed in CV-1 cells transfected with either androgen or and antiandrogenic activities [10]. This profile distinguishes glucocorticoid receptors and a reporter plasmid containing drospirenone from other synthetic progestogens currently mouse mammary tumor promotor virus or COS 1 cells used in OCs (Table 2) [5,6,18]. transfected with mineralocorticoid receptor and the identical viral promotor [10]. The results showed that (1) dro- spirenone and progesterone inhibit aldosterone-induced 3. Pharmacology and bioactivity mineralocorticoid activity and weakly induce reporter gene transcription on their own; (2) both progestogens have no The progestational activity of drospirenone has been androgenic activity but display antiandrogenic activity